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牽?；ㄅcRNA干擾
點擊次數(shù)：1314 發(fā)布時間：2017-7-4
NAi現(xiàn)象的發(fā)現(xiàn)，是在外源的多拷貝轉基因被引入牽牛花后所激起的一個特定序列的基因沉默響應。RNAi導致了封面上的花的雙色彩圖案。Ａｒｇｏｎａｕｔｅ是RNAi效應復合體中的標志組分，本期封面上登載了它的晶體結構，其中ＰＡＺ域用藍色顯示，ＰＩＷＩ域用紫色顯示。本期《科學》還刊登了曾于７月29日發(fā)表的兩篇有關的研究文章，以及一篇相關的研究評述。
Argonaute Journeys into the Heart of RISC
Erik J. Sontheimer and Richard W. Carthew
Identifying the "slicer" component of the RNA-induced silencing complex (RISC) complex has been a major goal of those interested in the RNA interference pathway of GENE silencing. In their Perspective, Sontheimer and Carthew discuss a pair of recent studies (Liu et al., Song et al.) that identify the protein Argonaute2 as the slicer element of RISC that cleaves target messenger RNAs.
Argonaute2 Is the Catalytic Engine of Mammalian RNAi
Jidong Liu,1* Michelle A. Carmell,1,2* FABIola V. Rivas,1 Carolyn G. Marsden,1 J. Michael Thomson,3 Ji-Joon Song,1 Scott M. Hammond,3 Leemor Joshua-Tor,1 Gregory J. Han
Gene silencing through RNA interference (RNAi) is carried out by RISC, the RNA-induced silencing complex. RISC contains two sigNature components, small interfering RNAs (siRNAs) and Argonaute family proteins. Here, we show that the multiple Argonaute proteins present in mammals are both biologically and biochemically distinct, with a single mammalian family member, Argonaute2, being responsible for messenger RNA cleavage activity. This protein is essential for mouse development, and cells lacking Argonaute2 are unable to mount an experimental response to siRNAs. Mutations within a cryptic ribonuclease H domain within Argonaute2, as identified by comparison with the structure of an archeal Argonaute protein, inactivate RISC. Thus, our evidence supports a model in which Argonaute contributes "Slicer" activity to RISC, providing the catalytic engine for RNAi.
1 Cold Spring Harbor Laboratory, Watson School of Biological sciences, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2 Program in genetics, Stony Brook University, Stony Brook, NY 11794, USA.
3 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Crystal Structure of Argonaute and Its Implications for RISC Slicer Activity
Ji-Joon Song,1,2 Stephanie K. Smith,2 Gregory J. Hannon,1 Leemor Joshua-Tor1,2*
Argonaute proteins and small interfering RNAs (siRNAs) are the known signature components of the RNA interference effector complex RNA-induced silencing complex (RISC). However, the identity of "Slicer," the enzyme that cleaves the messenger RNA (mRNA) as directed by the siRNA, has not been resolved. Here, we report the crystal structure of the Argonaute protein from Pyrococcus furiosus at 2.25 angstrom resolution. The structure reveals a crescent-shaped base made up of the amino-terminal, middle, and PIWI domains. The Piwi Argonaute Zwille (PAZ) domain is held above the base by a "stalk"-like region. The PIWI domain (named for the protein piwi) is similar to ribonuclease H, with a conserved active site aspartate-aspartate-glutamate motif, strongly implicating Argonaute as "Slicer." The architecture of the molecule and the placement of the PAZ and PIWI domains define a groove for substrate binding and suggest a mechanism for siRNA-guided mRNA cleavage.
1 Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2 Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.